Post-transcriptional control of gene expression following toxic injury

Lead Research Organisation: MRC Toxicology Unit

Abstract

Protein synthesis is the process by which the information in the genetic material in the cell, DNA, is converted via an intermediary substrate mRNA, into proteins. For proteins to be synthesised, the mRNA must interact with a large complex called the ribosome which consists of RNAs and proteins. Ribosomes are able to decode the genetic information that is held in the mRNA and carry out the synthesis of the proteins. When mammalian cells are exposed to toxic agents that can damage the cell one of the first things to happen is that protein synthesis is almost totally switched off. This is part of the cell’s defensive mechanism, since it allows the cell to repair the damage and recover from toxic injury. However, whilst overall protein synthesis is decreased under these types of conditions, certain proteins still need to be made that allow the cell to recover from the damage. We have shown previously that following treatment of cells with a range of toxic agents, for example, a commonly used chemotherapeutic drug called cisplatin, there is increased synthesis of proteins that are required to repair the damage that is caused to the DNA by this compound. We have also found that under these conditions the cells use a different mechanism to synthesise proteins. The important questions that needs to be addressed are what are the proteins that are synthesised under these conditions and how are they regulated following toxic exposure.

Technical Summary

Following toxic cellular insult mediated by a range of agents (including UVB exposure, cisplatin and TNF related apoptosis inducing ligand, TRAIL, asbestos exposure) there is a reprogramming of protein synthesis. This reprogramming event occurs in addition to transcriptional control, although in comparison to transcription control post-transcriptional regulation has been less studied. From the systems examined thus far, the data suggest that following toxic injury subsets of mRNAs are co-ordinately regulated at a post-transcriptional level. The overall spectrum of mRNAs that are selectively translated under these conditions is specific to the type of toxic injury imposed, thus forming an essential part of the cellular response to toxic exposure. The overall aims of this programme are: A) to combine post-transcriptional and transcriptional profiling data obtained following exposure to different classes of toxic agents, to generate new models to accurately predict the effects of toxic insult; B) to carry out a detailed analysis on the RNA elements and their cognate binding proteins that permit the selective protein synthesis following toxic exposure to determine the mechanistic basis for the response; C) to examine ways in which the response to toxic injury can be modulated to enhance the efficacy of cytotoxic agents.

Publications


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Blagden SP (2011) The biological and therapeutic relevance of mRNA translation in cancer. in Nature reviews. Clinical oncology



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Cannell IG (2010) p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. in Proceedings of the National Academy of Sciences of the United States of America






 
Description MRC Strategy Board
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Member of BBSRC Appointments panel
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Membership of DSM committee at AZ
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description SIAC
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description BBSRC project grant, Title translational regulation of TOP-containing mRNAs
Amount £605,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2011 
End 05/2014
 
Description BBSRC project grant: Defining novel mechanisms of mRNA translational control on cold shock
Amount £340,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2012 
End 01/2015
 
Description Joint Investigator award
Amount £900,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2016 
End 08/2021
 
Description Mouse models to understand the role of eIF4B in the pathogenesis of diffuse large B cell lymphoma
Amount £290,000 (GBP)
Funding ID 14022 
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2015 
End 12/2017
 
Description Professorial Fellowship
Amount £806,732 (GBP)
Funding ID BBH)24980/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2008 
End 10/2013
 
Description Project grant
Amount £400,000 (GBP)
Funding ID 091595 
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2010 
End 12/2014
 
Description Understanding the role of eIF4B in the pathogenesis of diffuse large B cell lymphoma
Amount £170,000 (GBP)
Funding ID 14023 
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2015 
End 12/2017
 
Description Wellcome Trust collaborative award
Amount £2,000,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2016 
End 09/2021
 
Description project grant (Co applicant with Cambridge)
Amount £180,000 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2012 
End 05/2015
 
Description project grant: Post-transcriptional regulation of the DNA repair response
Amount £187,000 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2010 
End 06/2013
 
Description APC and translation 
Organisation Cancer Research UK (CRUK)
Department The Beatson Institute for Cancer Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution Polysome profiling, Mice from Prof O Sampson
Collaborator Contribution Provided mice and intellectual input
Impact none yet
Start Year 2010
 
Description Professor Peter Fischer 
Organisation University of Nottingham
Department School of Pharmacy Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution novel eIF4E inhibitors
Collaborator Contribution development of new assays
Impact will lead to publications
Start Year 2010
 
Description Translational profiling during coldshock 
Organisation University of Kent
Department School of Biosciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution A joint project on cold shock has been carried out.
Impact This has lead to a BBSRC funded grant award and one joint publication. 3 further papers are planned
Start Year 2009
 
Description Brooke Priory school visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 30 children spent a day making DNA in the Unit.
They had 2 lectures one of which I presented

About half the children decided that they would like to be scientists but they were only 10!
Year(s) Of Engagement Activity 2012
 
Description CSH Conference on Translational Control, Cold Spring Harbor Laboratory, USA 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Lab attended CSH Translational control. We had 4 posters and one talk.

Stimulated interest in the work of the lab and promoted work in the Unit
Year(s) Of Engagement Activity 2014
 
Description Eurotox 2014, Edinburgh 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation poster presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Members of my lab attended EuroTox and presented 3 posters.

Stimulated interest in research carried out in the MRC Toxicology Unit
Year(s) Of Engagement Activity 2014
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk to 80 members of the public as part of the Leicester University Genie Scheme.

Well received talk
Year(s) Of Engagement Activity 2011
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 300 attended lecture on Toxicology
Year(s) Of Engagement Activity 2015
 
Description RNA UK cumbria conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact stimulated interest in our research

Amandine Bastide from my laboratory was awarded a prize for best talk
Year(s) Of Engagement Activity 2014
 
Description Research Talk (Leeds) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Research Talk on protein synthesis control
Year(s) Of Engagement Activity 2016
 
Description Research talk (Cambridge) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Research talk,
Year(s) Of Engagement Activity 2016
 
Description School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk about science and the theory of knowledge to 6th form students

6th form students asked for summer placements in the MRC Unit
Year(s) Of Engagement Activity 2011
 
Description School lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Regional
Primary Audience Schools
Results and Impact Lecture on theory of knowledge and how scientific theories are developed to year 11 IB students

Increased appreciation of scientific thought.
Year(s) Of Engagement Activity 2012
 
Description School visit Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave a talk on Toxicology to Oxford high school for girls
Year(s) Of Engagement Activity 2016
 
Description School visit to the Unit of 4 16 year olds for a week work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact School visit by 4 16 year olds students who carried out work experience for one week in my laboratory
Year(s) Of Engagement Activity 2016
 
Description Seminar Human Genetics Unit Edinburgh 
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Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact MRC Human Genetics Unit, Edinburgh

Interest in work from colleagues
Year(s) Of Engagement Activity 2013
 
Description Seminar Queens University Belfast 
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Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact September 24 - Centre for Cancer Research & Cell Biology, Queens University, Belfast.

Interest in research area
Year(s) Of Engagement Activity 2013
 
Description Seminar Sanquin Research 
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Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 100 researchers attended talk. Seminar and Masterclass, Sanquin Research & Landsteiner Lab., Amsterdam

new collaborations
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Description Seminar UCL 
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Results and Impact research seminar
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Description Seminar UCL London 
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Results and Impact interest in research

Requests for further data
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Description Seminar University of Surrey 
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Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact May 23 - Dept. of Microbiological & Cellular Sciences, University of Surrey

new collaborations
Year(s) Of Engagement Activity 2013
 
Description Seminar University of Tor Vergata Rome 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Pharmacy Summer School, University of Tor Vergata, Rome

Attended by students who showed interest in the research area
Year(s) Of Engagement Activity 2013
 
Description Seminar to Institute of Structural and Molecular Biology, UCL, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact gave a research seminar

more collaborations
Year(s) Of Engagement Activity 2014
 
Description Seminar to University of Rome Tor Vergata 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Research seminar, many questions

important new interactions
Year(s) Of Engagement Activity 2014
 
Description Seminar to University of Würzburg, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Research talk stimulated interest

formal collaborations established
Year(s) Of Engagement Activity 2014
 
Description TV interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Gave TV interviews about the Unit's research to ITN, BBC East midlands todays, ITV Central, Sky News and Chanel 5 news.

Huge interest in the Unit's science from the public.
Year(s) Of Engagement Activity 2013
 
Description Translation UK, Leicester 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation workshop facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Translation UK organizer. Over 150 people attended the conference.

collaborations, stimulated discussions etc.
Year(s) Of Engagement Activity 2014
 
Description Unit Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Over 500 members of the pubic visited the Unit

Member of the public were very appreciative.
Students asked to come and carry out work experience in the Unit
Year(s) Of Engagement Activity 2013
 
Description conference Roscoff 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk to colleagues,

new collaborations established
Year(s) Of Engagement Activity 2012
 
Description school visit to Uint 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 40 students attended the Unit, were shown how to make DNA in the laboratories and given talks on Toxicology

School found it stimulated interest in science
Year(s) Of Engagement Activity 2011